Repeat hepatic resection versus percutaneous ablation for the treatment of recurrent hepatocellular carcinoma: meta-analysis

Abstract Background The efficacy of repeat hepatic resection (rHR) in the treatment of recurrent hepatocellular carcinoma compared with radiofrequency or microwave ablation after resection of the primary tumour remains controversial. A systematic review and meta-analysis were performed to compare the safety and efficacy of these procedures. Methods PubMed, Embase, Scopus, Cochrane Library, and China National Knowledge Infrastructure databases were systematically searched to identify related studies published before 10 October 2021. Overall and recurrence-free survival after different treatments were compared based on pooled hazard ratios with a random-effects model. Results Two randomized clinical trials and 28 observational studies were included, involving 1961 and 2787 patients who underwent rHR and ablation respectively. Median perioperative mortality in both groups was zero but patients in the rHR group had higher median morbidity rates (17.0 per cent) than those in the ablation group (3.3 per cent). rHR achieved significantly longer recurrence-free survival than ablation (HR 0.79, 95 per cent c.i. 0.70 to 0.89, P < 0.001), while both groups had similar overall survival (HR 0.93, 95 per cent c.i. 0.83 to 1.04, P = 0.18). Conclusion rHR and ablation based on radio- or microwaves are associated with similar overall survival in patients with recurrent hepatocellular carcinoma after resection of the primary tumour.


Introduction
Hepatic resection and radiofrequency or microwave ablation are commonly used to treat patients with hepatocellular carcinoma (HCC) satisfying the Milan criteria (single nodule 5 cm or less, or up to three nodules less than 3 cm each, and no macrovascular invasion or distant metastasis) 1,2 . The 5-year recurrence rate is as high as 49-60 per cent among patients with early-stage HCC 3,4 . Given that HCC recurrence remains the leading cause of HCC-related deaths 5 , more effective treatment strategies are needed for recurrent HCC. Common therapies include repeat hepatic resection (rHR), radiofrequency or microwave ablation, liver transplantation, transarterial chemoembolization (TACE), radiotherapy, and administration of tyrosine kinase inhibitors. Although there are no definitive recommendations for the treatment of recurrent HCC [5][6][7] , rHR, ablation, and liver transplantation are considered the main curative approaches. The clinical application of liver transplantation is limited due to strict indications, lack of donors, and high treatment costs. In addition, meta-analyses on the safety and efficacy of rHR and ablation in patients with recurrent HCC within or beyond Milan criteria have provided conflicting conclusions [8][9][10][11][12][13] . In the present study, an updated systematic review with meta-analysis was performed to make recent comparisons of the safety and efficacy of rHR and microwave or radiofrequency ablation to treat recurrent HCC.

Study search
This meta-analysis was conducted according to the PRISMA Guidelines (Supplementary Material) 14 . A systematic search of PubMed, Embase, Scopus, Cochrane Library, and China National Knowledge Infrastructure databases was performed by two independent reviewers to retrieve articles published before 15 April 2021 using the following keywords: 'hepatocellular carcinoma' AND ('recurrence' OR 'recurrent') AND ('repeat hepatectomy' OR 'repeat hepatic resection', OR 're-hepatectomy') AND 'ablation'. The same search was repeated in October 2021 to identify studies published between 15 April and 10 October 2021. The search results were screened based on titles and abstracts, and appropriate articles were selected based on inclusion and exclusion criteria (see following section). The reference lists of relevant publications were also reviewed manually to identify additional potentially relevant articles.

Inclusion and exclusion criteria
To be eligible for inclusion, studies had to involve patients with recurrent HCC after curative resection, followed by treatment with rHR, involving microwave ablation or radiofrequency ablation; compare the safety and/or efficacy of ablation and rHR for recurrent HCC; involve patients with recurrent HCC without macrovascular invasion or extrahepatic metastasis; and report one or more of the target outcomes of overall survival (OS), recurrence-free survival (RFS), or perioperative morbidity, or mortality. Eligible studies were included in the present meta-analysis even if patients received TACE or other treatments after rHR or ablation. In the case of studies with overlapping patient samples, only the largest study was included.
Exclusion criteria included studies comparing hepatectomy and ablation for primary or metastatic liver cancer; single-arm studies or studies where each treatment arm contained fewer than 10 patients; and studies in which patients received other therapies, such as TACE, radiotherapy, or tyrosine kinase inhibitors after HCC recurrence and before rHR or ablation.

Quality assessment and data extraction
The eligibility of the included studies was assessed before data extraction. The quality of the randomized and non-randomized clinical trials (RCTs) was assessed, by use of the Cochrane Handbook for Systematic Evaluation of Interventions or the Newcastle-Ottawa Scale 15 . The following data were extracted independently by the two reviewers: first author name, sample size, age, sex, number and size of recurrent tumours, time to first recurrence, presence of liver cirrhosis, follow-up interval, perioperative morbidity, and mortality, as well as OS, RFS, and their hazard ratios (HRs). Disagreements were resolved by discussion or assessment by a third author.

Primary and secondary outcomes
The primary outcome was OS, defined as the interval from rHR or ablation to treat recurrent HCC until death from any cause or until last follow-up. Secondary outcomes were perioperative mortality or morbidity and RFS, which was defined as the interval from rHR or ablation to treat recurrent HCC until HCC re-recurrence or death.

Statistical analysis
Meta-analysis was performed with Review Manager version 5.3 (Cochrane Collaboration, Oxford, UK). Continuous data were reported as medians and quartiles, while differences between the two treatment groups were assessed for significance with the Mann-Whitney U test. Statistical heterogeneity was assessed with the I 2 test. OS and RFS between the two groups were compared based on pooled HRs calculated with a random-effects model. Differences with P , 0.05 were considered statistically significant.
Whenever possible, unadjusted, or adjusted HRs were extracted from the original text of each study or estimated from Kaplan-Meier curves as described 16 . If both unadjusted and adjusted HRs were reported, the adjusted ratios were used. Median OS and RFS at 1, 3, and 5 years were estimated with bubble charts, where the size of each bubble represented the sample size of the given study 17 . The impact of individual studies on aggregate estimates was assessed through sensitivity analysis, in which the analysis was repeated after removing one study at a time. Funnel plots were also used to identify potential publication bias.

Study selection
After searching the indicated databases, a total of 767 studies were identified as potentially eligible, of which 185 were duplicates. Of the remaining 582 studies, 540 were excluded based on review of titles and abstracts, leaving 42 for full-text review. Of these 42 studies, 27 met the inclusion criteria and the rest were excluded due to duplicate publication or because they were single-arm studies, studies where each treatment arm contained fewer than 10 patients, studies with no outcome data, or studies on patients with recurrent HCC with macrovascular invasion. Two of the 27 selected studies were RCTs 18,19 and 25 were observational comparisons  . Three additional studies were identified during the repeat literature search [45][46][47] . Overall, 30 studies were included in the meta-analysis (Fig. 1).

Characteristics of included studies
One of the selected studies was conducted in Germany 23 and the rest in China, Japan, Korea, Taiwan, Hong Kong, and Singapore 18-22,24-47 . Data were collected from 4748 patients, of whom 1961 were treated with rHR and 2787 with ablation ( Table 1). Only one study involving 66 patients reported the use of microwave ablation 43 , whereas the remaining 26 applied radiofrequency ablation [44][45][46][47] . According to the Cochrane Handbook for Systematic Evaluation of Interventions, both RCTs were of high quality ( Table S1). The Newcastle-Ottawa Scale score was above 5 for all non-RCTs, indicating acceptable quality (Table S2).

Sensitivity analysis and publication bias
Sensitivity analysis showed that excluding any one of the studies, including the one reporting microwave ablation 43 , did not significantly affect the pooled results (Figs. S1 and S2). Similar results were obtained when all studies were meta-analysed with a random-or fixed-effect model. However, visual inspection of

Study or subgroup
Chan et al. 20 Chen et al. 22 Chen et al. 21 Chua et al. 60 Eisele Wei et al. 46 Xia et al. 39 Zhang et al. 43 Zhong

Discussion
Postoperative tumour recurrence is the most important factor affecting the long-term survival of patients with HCC after hepatic resection. Previous studies have shown that rHR and ablation are the most effective methods for treating recurrent HCC 8,13,48 although the 5-year re-recurrence rate remains high.
In the present meta-analysis, safety, and efficacy of rHR and ablation were compared using a larger sample than in previous studies [8][9][10][11][12][13] . Both therapeutic approaches provided similar OS, but rHR was associated with longer RFS at the expense of higher perioperative morbidity.
Earlier meta-analyses involving studies with small samples indicated that radiofrequency and microwave ablation have similar efficacy for primary untreated HCC 49,50 , suggesting that these two percutaneous techniques could be aggregated in the present analysis. Of the 30 studies selected, only 1 43 compared the efficacy of microwave ablation and rHR reporting similar OS, but slightly higher RFS for rHR.
The present results are consistent with the findings of previous meta-analyses [51][52][53] , but show higher median 5-year OS (.50 per cent) after both treatments than previously reported (35.2 per cent and 48.3 per cent for rHR and for ablation respectively) 8 . Four small meta-analyses concluded that rHR was associated with better OS than ablation [10][11][12][13] , whereas another study reported similar RFS for the two treatments 9 . This discrepancy may be explained by the smaller sample size of previous studies. Chan et al. 20 Chen et al. 22 Chua et al. 60 Eisele et al. 23 Feng et al. 24 Liu et al. 18 Lu et al. 31 Matsumoto et al. 47 Peng et al. 32 Ren et al. 33 Song et al. 35 Sun et al. 36 Wei et al. 46 Xia et al. 39 Yan et al. 40 Zhang et al. 43  A recent meta-analysis of 7 RCTs and 18 matched non-RCTs concluded that hepatic resection and radiofrequency ablation were associated with similar OS for patients with primary untreated HCC satisfying the Milan criteria, but that hepatic resection may be associated with better RFS and lower rate of local recurrence 1 . Consistent with these results, in this meta-analysis both treatments achieved similar 1-, 3-, and 5-year OS in patients with recurrent HCC, whereas rHR was associated with considerably higher RFS. In previous studies, 14.9 per cent of patients with HCC showed insufficient margins 54 and shorter time to recurrence after ablation 19,44 . The significant difference in RFS between the two treatment groups in the present meta-analysis might be explained by incomplete ablation. In contrast, the similar OS values might reflect the fact that some patients received one or more additional treatments after tumour recurrence or re-recurrence 44 , that led to improved OS.
Although radiofrequency ablation is commonly used to treat HCC with tumour diameter more than 3 cm, it is currently considered best for HCC tumours less than 3 cm 55 . Radiofrequency ablation removes HCC with diameters of 3-5 cm much less effectively than in smaller tumours, translating to greater risk of local recurrence 56 . The efficacy of radiofrequency ablation also decreases gradually with increasing tumour number and diameter 57 . These findings suggest that tumour diameter should be considered when selecting treatment options for recurrent HCC. Unfortunately, subgroup analyses based on tumour diameter or number was not possible in the present meta-analysis, as most of the included studies reported only tumour stage.
The present results should be interpreted carefully considering several limitations. Most of the included studies were observational, indicating that additional well designed RCTs should be conducted in the future. Moreover, rHR and ablation may have different indications for recurrent HCC depending on tumour diameter, location, and patient characteristics. As most of the studies reported only data for recurrent HCC within Milan criteria, these results may not be generalizable to other patients. Patients in the included studies may have received one or more additional treatments after rHR or ablation, which may have affected their prognosis. For instance, several tyrosine kinase and immune-checkpoint inhibitors have recently been identified as firstor second-line therapy for patients with advanced or unresectable HCC [58][59][60][61] . Thus, the combination of rHR or local ablation with such inhibitors may improve the survival of patients with recurrent HCC. Finally, potential publication bias was observed in the funnel plots. Future meta-analysis with larger sample size may change the findings of the present study.
Despite these limitations, this meta-analysis provides evidence that rHR and local ablation are associated with similar OS in patients with recurrent HCC. rHR seems to be associated with better RFS, whereas local ablation leads to lower perioperative morbidity. These nuances highlight the need for individualized, multidisciplinary strategies when treating recurrent HCC.